Our studies are directed at understanding the mechanism by which Herpes-Simplex Virus-type 1 (HSV-1) infected targets are recognized and lysed by human natural killer (NK) cells. In these studies, both the heterogeneity of the effector cell population as well as sensitivity of the target cell itself to lysis will be considered. To investigate the heterogeneity at the effector cell level, studies will compare the effector cells which lyse HSV-infected fibroblasts to those which lyse HSV-1 infected lymphoblastoid cells and to the effectors which lyse K562 erythroleukemic cells. These effectors will be compared at the level of cell surface phenotype using monoclonal antibodies and in cold competition studies. To study the role of viral products and, in particular, viral glycoproteins in conferring susceptibility of infected cells to lysis, we will continue our investigations using viral mutants and biochemical inhibitors of various stages of virus replication. Virus mutants which fail to produce either alpha, beta, or gamma proteins will be studied to determine the effect of absence of these gene products on conferring susceptibility of targets to lysis. Metabolic inhibitors will include inhibitors of DNA synthesis as well as inhibitors of transcription and/or translation. These experiments will also include determinations of the susceptibility of the infected versus uninfected targets to cytotoxic factors including NK cytotoxic factor and rat cytotoxic granules. (LB)